Because human papillomavirus (HPV) infections appear to be causally linked to most cervical intraepithelial neoplasia (CIN) and cervical carcinoma, it is important to identify determinants of HPV-associated cervical disease. A growing body of evidence suggests an important role for the major histocompatibility complex (MHC) in the etiology of cervical dysplasia and cancer. Further studies in this area are needed to determine the relationship between host-virus interaction and the risk for cervical disease. In addition to understanding host factors, we also need to understand the population dynamics of HPV infections. Currently, HPV "types" have been used as the exposure measure for HPV-associated risk for invasive cervical carcinoma. This level of exposure determination has not provided us with useful prognostic markers for determining risk of progression to invasive cervical carcinoma. Virtually no information is available concerning specific HPV sequences within HPV types associated with risk for invasive cervical carcinoma or presumed precursor lesions. Furthermore, sequence diversity of HPVs, the potential significance of HPV variants and subtypes, and relationships between HPV types have been given little consideration as factors important for determining risk for cervical disease. This grant application requests funding for studies that will examine host- and viral-specific risk factors of HPV-associated cervical disease. We have previously identified HPV-specific MHC associations with severe dysplasia/ClS and invasive cervical carcinoma in case-control studies of Hispanic women. We will characterize HLA class l and II loci in case-control studies of in situ and invasive cervical cancer in Hispanic and non-Hispanic white women from the same geographic location. We will also consider HPV sequence-specific risk factors for cervical disease. We have previously observed an amino acid change in the HPV-16 E6 open reading frame that is associated with high grade squamous intraepithelial lesions. We will examine this observation in a blinded investigation using specimens obtained through an ongoing longitudinal cohort study of HPV and cervical disease being conducted by the NCl. The proposed studies will form a basis for elucidating specific mechanisms of HPV-associated cervical cancer.